沈阳药科大学杨静玉等研究人员合作发现，单剂量甲基苯丙胺通过DA介导的对PrL^Glu活性的过度抑制可损害小鼠的ORM检索。相关论文于2024年6月24日在线发表于国际学术期刊《中国药理学报》。

研究人员揭示了单剂量甲基苯丙胺（METH）对小鼠物体识别记忆（ORM）检索的影响及其内在机制。研究人员发现，单剂量METH给药（2mg/kg，静脉注射）会显著损害小鼠的ORM检索。METH治疗小鼠的纤维光度记录显示，在ORM检索过程中，前边缘皮层谷氨酸能神经元（PrL^Glu）的活性明显降低。PrL^Glu或从腹侧CA1到PrL的谷氨酸能投射（vCA1^Glu-PrL）的化学激活可挽救ORM检索障碍。纤维光度记录显示，经METH处理的小鼠PrL中的多巴胺（DA）水平显著升高，将D2受体（D2R）拮抗剂舒必利（0.25μg/边）微量注入PrL可缓解ORM检索障碍。

在含有PrL的脑片中进行的全细胞记录显示，METH治疗小鼠的PrL^Glu固有兴奋性和基础谷氨酸能突触传递显著降低，在METH治疗小鼠的PrL中微量注入舒必利可逆转固有兴奋性的降低。因此，单剂量METH给药导致的ORM恢复受损可能是由于PrL^Glu活性降低，也可能是由于D2R上的DA活性过高。选择性激活PrL^Glu或vCA1^Glu-PrL可能是METH诱导的认知功能障碍的一种潜在治疗策略。

据介绍，METH是一种被滥用的精神兴奋剂，通过长期甚至单剂量接触会损害认知能力，但动物实验却显示其对记忆缺陷的影响相互矛盾。

附：英文原文

Title: Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrLGlu activity

Author: Ma, Jian-chi, Che, Xiao-hang, Zhu, Xiao-na, Ren, Ao-xin, Hu, Yue, Yang, Cheng-li, Xu, Zhong-tian, Li, Yu-ting, Wu, Chun-fu, Yang, Jing-yu

Issue&Volume: 2024-06-24

Abstract: Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25μg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrLGlu intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.

DOI: 10.1038/s41401-024-01321-9

Source: https://www.nature.com/articles/s41401-024-01321-9